Project Summary Alcohol Use Disorders (AUDs) are currently positioned as the 3rd leading cause of preventable death in the United States, contributing to 88,000 deaths per year. In 2019, total allied costs of medical care associated with AUD exceeded $224 billion. A common goal among treatment efforts in AUD is to prevent relapse to drinking. Although several pharmacological treatments are available, adherence to these treatments is low and approximately 60% of individuals who engage in them relapse within 6 months. Further, these treatments modulate the brain in a relatively global fashion. Evidence from neuroimaging studies of AUD patients has shown that fronto-striatal neural-circuitry shows elevated activity in response to alcohol cues which may subsequently predict relapse. Thus, there is an emerging interest in developing novel, neural-circuit specific therapeutic tools to enhance AUD treatment outcomes. Transcranial magnetic stimulation (TMS) is one such non- invasive, neural-circuit specific tool. Through electromagnetic induction, repetitive pulses of TMS can be applied to the MPFC to change neural activity at the site of stimulation and can travel along intact white matter tracts to change neural activity in downstream connections such as the striatum. However, it is well known that individuals with AUD suffer from widespread reductions in gray matter volume (impacting the site of stimulation) as well as reductions in white matter integrity (impacting the tract between the MPFC and striatum). The primary goal of this F31 research proposal is to determine the influence of gray matter volume in the MPFC (Aim 1) and white matter integrity between the MPFC and striatum (Aim 2) on TMS associated change in MPFC- striatal activity in response to alcohol cues. Further, this proposal plans to integrate Aims 1 & 2 with clinical biomarkers for AUD such as gender and drinking severity to evaluate the relative contributions of these factors in TMS related change in alcohol cue-induced MPFC-striatal activity. This proposal is complimented by a training plan that includes 4 domains: neuroimaging analysis, scientific communication, clinical perspective of AUD, and multivariate statistics. This 2-year F31 fellowship will be analyzed by leveraging an existing data set from our laboratory. The parent clinical trial for this F31 proposal recruited 50 treatment-seeking individuals with AUD to receive MRI scans at baseline, followed by 10 days of real or sham TMS, followed by MRI scans after treatment, 1 month after treatment, and 2 months after treatment. Each MRI scan consisted of a high-resolution anatomical image (Aim 1), diffusion kurtosis imaging (Aim 2) and a functional MRI task to measure alcohol cue-induced functional connectivity in the MPFC-striatal circuit. Cutting-edge methodologies will be used to analyze the data presented in this proposal, including: voxel-based morphometry, electrical field modeling, diffusion kurtosis imaging, functional connectivity analysis, and multivariate statistics. The candidate will incorporate guidance from experts in neuroimaging and AUD (Drs. Hanlon and Jensen) to evaluate these aims.